DataSheet_1_Repolarization of Tumor-Infiltrating Myeloid Cells for Augmentation of CAR T Cell Therapies.pdf

Although CAR T cell therapies have proven to be effective in treating hematopoietic cancers, their abilities to regress solid tumors have been less encouraging. Mechanisms to explain these disparities have focused primarily on differences in cancer cell heterogeneity, barriers to CAR T cell penetration of solid tumors, and immunosuppressive microenvironments. To evaluate the contributions of immunosuppressive tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) on CAR T cell efficacies, we have exploited the ability of a folate-targeted Toll-like receptor 7 agonist (FA-TLR7-1A) to specifically reactivate TAMs and MDSCs from an immunosuppressive to pro-inflammatory phenotype without altering the properties of other immune cells. We report here that FA-TLR7-1A significantly augments standard CAR T cell therapies of 4T1 solid tumors in immune competent mice. We further show that co-administration of the FA-TLR7-1A with the CAR T cell therapy not only repolarizes TAMs and MDSCs from an M2-like anti-inflammatory to M1-like pro-inflammatory phenotype, but also enhances both CAR T cell and endogenous T cell accumulation in solid tumors while concurrently increasing their states of activation. Because analogous myeloid cells in healthy tissues ar not altered by administration of FA-TLR7-1A, no systemic activation of the immune system nor accompanying weight loss is observed. These data argue that immunosuppressive myeloid cells contribute prominently to the failure of CAR T cells to eradicate solid tumors and suggest that methods to reprogram tumor associated myeloid cells to a more inflammatory phenotype could significantly augment the potencies of CAR T cell therapies.

尽管CAR T细胞疗法在治疗造血系统肿瘤方面已证明其有效性，但其在消退实体肿瘤方面的能力却显得不尽人意。解释这些差异的机制主要聚焦于癌细胞异质性的差异、CAR T细胞穿透实体肿瘤的屏障，以及免疫抑制性微环境。为了评估免疫抑制性肿瘤相关巨噬细胞（TAMs）和骨髓来源的抑制细胞（MDSCs）对CAR T细胞疗效的贡献，我们利用了叶酸靶向的Toll样受体7激动剂（FA-TLR7-1A）的能力，特异性地使TAMs和MDSCs从免疫抑制型转变为促炎表型，而不会改变其他免疫细胞特性。我们在此报告，FA-TLR7-1A显著增强了免疫应答小鼠中4T1实体肿瘤的标准CAR T细胞疗法。我们进一步显示，FA-TLR7-1A与CAR T细胞疗法的联合应用不仅将TAMs和MDSCs从M2型抗炎表型重编程为M1型促炎表型，而且增强了CAR T细胞和固有T细胞在实体肿瘤中的积累，同时提高了它们的激活状态。由于FA-TLR7-1A的应用并未改变健康组织中的类似髓系细胞，因此未观察到全身免疫系统的激活以及伴随的体重减轻。这些数据表明，免疫抑制性髓系细胞显著影响了CAR T细胞根除实体肿瘤的失败，并暗示将肿瘤相关髓系细胞重编程为更具炎症表型的策略，可能会显著增强CAR T细胞疗法的效力。